Normal vocal fold vibration is crucially dependent upon tissue composition and viscoelasticity. When composition of the extracellular matrix (ECM) of the vocal fold cover (i.e. lamina propria - superficial and middle layers) is altered, vocal fold vibratory function can be severely disrupted due to alterations in tissue viscoelasticity. The dysphonias that result are generally difficult to treat effectively with current surgical paradigms and available biomaterials. Treatment failures have been ascribed to poor understanding of pathologic processes in the ECM, as well as suboptimal materials that may negatively affect vocal fold biomechanical properties. Accordingly, there is a clinical need for improved understanding of the pathophysiology of disrupted ECM and the development of advanced biomaterials that appreciate the biomechanical properties of the lamina propria. The long-term aim of this project is to engineer injectable products that promote wound repair and induce tissue regeneration, for treatment of scarring and other existing ECM defects of the lamina propria, exclusively for the superficial and middle layers. For the proposed funding period, we will specifically focus on chemically modified injectable synthetic ECM (sECM) hydrogels (HA derivatives) for tissue regeneration. These products will mimic and augment the existing ECM and yield optimal vocal fold ECM biomechanical properties. We will employ a unique combination of systematic chemical, biomechanical, in vitro and in vivo studies to resolve the complex interactions among cell and biomaterial characteristics, biomechanical properties and influences on cell behavior and the surgical requisites necessary to create a suitable clinical outcome. The overarching hypothesis is that manipulation of the ECM with injectable HA hydrogels and sols that have been encapsulated with living cells will yield optimal tissue composition and biomechanically optimal results. PUBLIC HEALTH RELEVANCE: Voice disorders affect an estimated 3-9% of Americans yearly and 29% of the population in their lifetime. Treatment for vocal fold scarring, a voice disorder caused by connective tissue or ECM injury or loss has been limited. The proposed research defines a novel and fundamental tissue engineering approach to repair vocal folds with longstanding damage due to injury or disease